1. Field of the Invention
The present invention is concerned with novel substituted N-carboxymethyl-aminoacylaminoalkanoic acid compounds which are effective inhibitors of angiotensin I converting enzyme. These novel compounds are, consequently, combined with pharmaceutically acceptable carriers to form pharmaceutical compositions of the present invention are are used in a method of treating hypertension.
Angiotensin II, a powerful vasoconstrictor hormonal peptide, is formed from the inactive angiotensin I by the action of angiotensin-converting enzyme. Recently, potent inhibitors of angiotensin-converting enzyme have been reported which are capable of lowering the blood pressure in hypertensive patients. The novel substituted N-carboxymethyl-aminoacylaminoalkanoic acid compounds of the present invention are also potent inhibitors of angiotensin-converting enzyme.
2. Brief Description of the Prior Art
U.S. Pat. Nos. 4,113,715; 4,129,571; and 4,154,960 disclose substituted acyl derivatives of amino acids which are useful as angiotension converting enzyme inhibitors. More specifically, these compounds are mercapto substituted acyl amino acids and derivatives thereof including the clinically effective antihypertensive compound, captopril, i.e., D-3-mercapto-2-methylpro-panoyl-L-proline.
The foregoing prior art compounds are not dipeptide derivatives as are the compounds of the present invention. Furthermore, these prior art compounds contain an essential sulfhydryl substituent or derivative thereof whereas those of the present invention do not. In addition, the dipeptide compounds of the present invention are unusual dipeptides whose N-terminus bears a carboxymethyl group which is preferably further substituted on the methyl group. In addition, the carboxyl group(s) may also be converted to ester, amide and salt derivatives. In effect, the compounds of the present invention are hybrids formed by fusing .alpha.-amino acids onto dipeptides by means of a nitrogen shared by these two part-structures. This structural arrangement is rare in the field of synthetic and natural peptides and is not suggested or disclosed by the mercaptoacyl type functions of the two prior art patents identified above.
German Patent Application Nos. 2704-985 and 2720-996 describe hypotensive carboxy-actyl-proline derivatives and (N)-carboxyalkanoyl amino acid derivatives; and German Patent Application No. 2810-261 describes thio-substituted (N)-propionylamino acid derivatives which are hypotensive angiotensin converting enzyme inhibitors.
However, none of these references show or suggest any of the compounds of the present invention, which contain the R.sup.3 functionality described herein.
An abstract of ACS meeting of 9-11-78 entitled "Superactive Analogs of the Angiotensin Converting Enzyme Inhibitor BPP.sub.9a Containing L-3,4-Dehydroproline" describes the use of dehydroproline on various peptides, none of which, however, are similar to the compounds of the present invention.
German Pat. No. 30 46 271 Al discloses optically active N-mercaptoalkanoylaminoacids which are useful as angiotensin converting enzyme inhibitors. Although this reference teaches that the claimed compounds have the same utility as those of the present invention, the compounds disclosed in the reference differ materially and significantly from those of the present invention especially since all of the reference compounds are mercapto-based.
Patchett et al., in "A New Class of Angiotensin-converting Enzyme Inhibitors", Nature, Vol. 288, No. 5788, pp. 280-283 (Nov. 20, 1980), describe certain N-carboxymethyldipeptides. However, the substituted N-carboxymethyl-(amino acid)pyrrolidinealkanoic acid compounds of the present invention are readily distinguishable by the presence of the R.sup.3 functionality described herein.